Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells.

Jarmila Lauková,Jiří Ehrmann,Mary Pat Moyer,Alena Hyršlová Vaculová,Jiřina Hofmanová,Alois Kozubík,Petr Sova,Jana Nekvindová,Yoshiaki Tsuji

doi:10.1371/journal.pone.0141020

Abstract

We demonstrated for the first time an outstanding ability of rosiglitazone to mediate a profound enhancement of LA-12-induced apoptosis associated with activation of mitochondrial pathway in human colon cancer cells. This effect was preferentially observed in the G1 cell cycle phase, independent on p53 and PPARγ proteins, and accompanied with significant changes of selected Bcl-2 family protein levels. Further stimulation of cooperative synergic cytotoxic action of rosiglitazone and LA-12 was demonstrated in the cells deficient for PTEN, where mitochondrial apoptotic pathway was more stimulated and G1-phase-associated dying was reinforced. Our results suggest that combined treatment with rosiglitazone and LA-12 might be promising anticancer strategy in colon-derived tumours regardless of their p53 status, and also favourable in those defective in PTEN function.

Highlights

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are involved in regulation of energy metabolism, cancer development and anti-inflammatory response [1]
The apoptotic response of HCT116 wt cells treated with the combination of rosiglitazone and LA-12 was associated with stimulation of the mitochondrial pathway, as indicated by the enhanced release of cytochrome c into the cytoplasm (Fig 2A), cleavage of caspase-9 (Fig 2B) and drop of membrane potential (MMP) (Fig 2C)
A functional role of mitochondria was further confirmed using HCT116 Bax-/- cells, where the apoptotic effects of the drug combination were significantly suppressed. This was demonstrated by a blockage of caspase-9 and PARP cleavage (Fig 2B), and drop of MMP (Fig 2C) in HCT116 Bax-/- cells treated by the combination of rosiglitazone and LA-12 compared to their wt counterparts

Summary

Introduction

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are involved in regulation of energy metabolism, cancer development and anti-inflammatory response [1]. A main role of PPARγ has been shown in the adipocyte differentiation and insulin sensitisation [2], PPARγ is well-known to affect growth and cell cycle [3, 4], differentiation [5] and apoptosis [6] of various types of cancer cells including colon. PPARγ expression is maintained at relatively high levels in numerous human colon cancer cell lines and primary colon tumours [7]. The mutations of PPARγ gene have been reported as rare. Rosiglitazone Enhances LA-12-Induced Apoptosis in Cancer Cells

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Conclusion